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Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/ SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment., Introduction Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis, which lead to progression of [...]

Aim: Behçet's disease (BD) can involve any gastrointestinal (GI) tract site. We analyzed the characteristics, risk factors, and treatment responses to upper GI (UGI) involvement in patients with BD. Methods: This retrospective cohort study analyzed UGI findings in 101 patients with BD who underwent endoscopy between April 2005 and December 2022 at the University of Tokyo Hospital. The patients were divided into two groups based on the presence or absence of UGI findings. Patient backgrounds, clinical symptoms, colonoscopy (CS) findings, and blood test findings were compared between the groups. Results: In total, 18.8% (19/101) of the patients had UGI lesions. The prevalence rates in the esophagus, stomach, and duodenum were 6.9%, 6.9%, and 8.9%, respectively. Of these 19 patients, BD treatment were intensified in 10 (52.6%) patients after esophagogastroduodenoscopy (EGD), and all showed improvement in symptoms or endoscopic findings. In the multivariate analysis, symptoms (OR: 37.1, P < 0.001), CRP > 1 mg/dL (OR: 11.0, P = 0.01), and CS findings (OR: 5.16, P = 0.04) were independent predictors of UGI involvement in BD patients. The prediction model for UGI involvement using these three factors was highly accurate, with an AUC of 0.899 on the ROC curve. In the subgroup analysis of intestinal BD, symptoms (OR: 12.8, P = 0.01) and ESR > 20 mm/h (OR: 11.5, P = 0.007) were independent predictors. Conclusions: EGD should be conducted in BD patients with high CRP, GI symptoms, and lower GI involvement, which leads to better management of BD in terms of improving symptoms and endoscopic findings. [ABSTRACT FROM AUTHOR]

Background and Aim: Convolutional neural network (CNN) systems that automatically detect abnormalities from small‐bowel capsule endoscopy (SBCE) images are still experimental, and no studies have directly compared the clinical usefulness of different systems. We compared endoscopist readings using an existing and a novel CNN system in a real‐world SBCE setting. Methods: Thirty‐six complete SBCE videos, including 43 abnormal lesions (18 mucosal breaks, 8 angioectasia, and 17 protruding lesions), were retrospectively prepared. Three reading processes were compared: (A) endoscopist readings without CNN screening, (B) endoscopist readings after an existing CNN screening, and (C) endoscopist readings after a novel CNN screening. Results: The mean number of small‐bowel images was 14 747 per patient. Among these images, existing and novel CNN systems automatically captured 24.3% and 9.4% of the images, respectively. In this process, both systems extracted all 43 abnormal lesions. Next, we focused on the clinical usefulness. The detection rates of abnormalities by trainee endoscopists were not significantly different across the three processes: A, 77%; B, 67%; and C, 79%. The mean reading time of the trainees was the shortest during process C (10.1 min per patient), followed by processes B (23.1 min per patient) and A (33.6 min per patient). The mean psychological stress score while reading videos (scale, 1–5) was the lowest in process C (1.8) but was not significantly different between processes B (2.8) and A (3.2). Conclusions: Our novel CNN system significantly reduced endoscopist reading time and psychological stress while maintaining the detectability of abnormalities. CNN performance directly affects clinical utility and should be carefully assessed. [ABSTRACT FROM AUTHOR]

Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. Kras activation and Pten deletion are observed in intestinal‐type gastric cancer, and Cdh1 mutation is associated with diffuse‐type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a Tff1‐Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomach, Tff1‐Cre‐mediated recombination was most evident in the pit lineage in the corpus and in entire antral glands; recombination was also observed in a few gastric chief and parietal cells. Outside the stomach, recombination was patchy throughout the intestines, and particularly frequently in the duodenum (Brunner glands), cecum, and proximal colon. In the stomachs of Tff1‐Cre;LSL‐KrasG12D mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue‐positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide‐expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Corpus‐derived organoids from Tff1‐Cre;LSL‐KrasG12D mice exhibited accelerated growth and abnormal differentiation with a loss of chief and parietal cell markers. Tff1‐Cre;Ptenflox/flox mice displayed similar changes to those seen in Tff1‐Cre;LSL‐KrasG12D mice, both with aberrant ERK activation within 3 months. In contrast, Tff1‐Cre;Cdh1flox/flox mice initially showed signet ring‐like cells that were rapidly lost with disruption of the mucosal surface, and later developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in Tff1‐Cre;Cdh1flox/flox mice was completely replaced by squamous epithelium which expanded from the forestomach. Tff1‐Cre mice offer an additional useful tool for studying gastric carcinogenesis both in vivo and in vitro. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim. Early diagnosis and evaluation of the severity of sigmoid volvulus are necessary for management and early intervention. We developed a new predictive classification system for sigmoid volvulus based on X-ray findings. Methods. We retrospectively analyzed 66 patients diagnosed with sigmoid volvulus using the electronic medical records at the Osaki Citizen’s Hospital and the University of Tokyo Hospital from 2008–2015. We classified patients according to the coffee-bean sign mesenteric axis on X-ray (AXIS classification: group A, 0–90°; group B, 90–135°; and group C, >135°). We examined the association between AXIS classification and severe sigmoid volvulus, intestinal necrosis, need for surgery, 30-day mortality, and length of stay using the Cochran–Armitage trend test. Results. In total, 66 patients were analyzed. They had a mean age of 76.9 years, and 47 (71.0%) were male. They were classified into three groups according to the AXIS classification system (group A, 40 patients; group B, 23 patients; and group C, 3 patients). Group C had a significantly higher frequency of severe sigmoid volvulus (100%) compared to group B (30%) and group A (15%). AXIS classification was significantly associated with the severity of sigmoid volvulus (p=0.003), necrosis (p=0.004), and need for surgery (p=0.001), but not with the 30-day mortality or the length of stay. Conclusions. We developed the AXIS classification system to predict the severity of sigmoid volvulus. This new classification system may facilitate triage and therapeutic decision-making for sigmoid volvulus patients. [ABSTRACT FROM AUTHOR]

Background and Aims Disturbance of intestinal homeostasis is associated with the development of inflammatory bowel disease [IBD], and TGF-β signalling impairment in mononuclear phagocytes [MPs] causes murine colitis with goblet cell depletion. Here, we examined an organoid–MP co-culture system to study the role of MPs in intestinal epithelial differentiation and homeostasis. Methods Intestinal organoids were co-cultured with lamina propria leukocytes and bone marrow–derived dendritic cells [BMDCs] from CD11c-cre Tgfbr2 fl/fl mice. Organoid–MP adhesive interactions were evaluated by microscopy, RT-PCR, and flow cytometry. Murine colitis models (dextran sodium sulphate [DSS], CD11c-cre Tgfbr2 fl/fl , T-cell-transfer) were used for histological and immunohistochemical analysis. Anti-E-cadherin antibody treatment or CD11c+-cell-specific CDH1 gene deletion were performed for E-cadherin neutralization or knockout. Colonic biopsies from patients with ulcerative colitis were analysed by flow cytometry. Results Intestinal organoids co-cultured with CD11c+lamina propria leukocytes or BMDCs from CD11c-cre Tgfbr2 fl/fl mice showed morphological changes and goblet cell depletion with Notch signal activation, analogous to CD11c-cre Tgfbr2 fl/fl colitis. E-cadherin was upregulated in CD11c+MPs, especially CX3CR1+CCR2+monocytes, of CD11c-cre Tgfbr2 fl/fl mice. E-cadherin–mediated BMDC adhesion promoted Notch activation and cystic changes in organoids. Anti-E-cadherin antibody treatment attenuated colitis in CD11c-cre Tgfbr2 fl/fl and T-cell–transferred mice. In addition, E-cadherin deletion in CD11c+cells attenuated colitis in both CD11c-cre Tgfbr2 fl/fl and DSS-treated mice. In patients with ulcerative colitis, E-cadherin expressed by intestinal CD11c+leukocytes was enhanced compared with that in healthy controls. Conclusions E-cadherin–mediated MP–epithelium adhesion is associated with the development of colitis, and blocking these adhesions may have therapeutic potential for IBD. [ABSTRACT FROM AUTHOR]

Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21Cip1 axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53 -mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible "hit-and-run mechanism" of H. pylori CagA for gastric carcinogenesis. [Display omitted] • PAR1b-mediated phosphorylation is required for nuclear translocalization of BRCA1 • CagA-mediated PAR1b kinase inhibition induces BRCAness by reducing nuclear BRCA1 • CagA-activated Hippo signaling prevents death of cells with BRCAness-induced DSBs • BRCA signature is created by cyclic expression of CagA in cells with defective p53 Imai et al. reveal that phosphorylation of BRCA1 by the polarity-regulating kinase PAR1b plays a critical role in the nuclear delivery of BRCA1 and H. pylori CagA-mediated PAR1b kinase inhibition, which impairs nuclear accumulation of BRCA1, elicits BRCAness and BRCAness-associated genomic instability that, in conjunction with the loss of p53, may contribute to the development of CagA-directed hit-and-run gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer. We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-Cre ERT mice. Wnt signaling activation, marked by Axin2 , was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19+ luminal surface BECs showed gradual replacement by CK19– cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal–activating niche. Notably, introduction of PTEN deletion into Axin2+ PBG cells, but not CK19+ luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor. A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma. [Display omitted] [ABSTRACT FROM AUTHOR]

The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling. [ABSTRACT FROM AUTHOR]

In Asia, the incidences of Helicobacter pylori infection and gastric cancer are high, but their association with autoimmune gastritis (AIG) is unclear. This was a retrospective cohort study of patients endoscopically diagnosed with chronic gastritis between 2005 and 2017. AIG was diagnosed according to anti-parietal cell antibody positivity. Laboratory, histological findings, and gastric cancer incidence were compared between AIG and non-AIG patients. The AIG group had more females and a higher rate of thyroid disease. Serum levels of gastrin were significantly higher in AIG patients (mean 1412 and 353 pg/mL, p < 0.001). The endoscopic findings included a significantly higher percentage of corpus-dominant atrophy in AIG (31.67%) than in non-AIG (7.04%) patients (p < 0.001). Clusters of ECL cells were observed in 28% of AIG patients and 7% of non-AIG patients (p = 0.032). The cumulative incidence of gastric cancer at 5 and 10 years was 0% and 0.03% in the AIG group and 0.03% and 0.05% in the non-AIG group, and no significant difference in gastric cancer incidence was observed. Despite significant differences in gastrin levels between AIG and non-AIG patients, there was no evidence of an impact of AIG on the incidence of gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric chief cells, a mature cell type that secretes digestive enzymes, have been proposed to be the origin of metaplasia and cancer through dedifferentiation or transdifferentiation. However, studies supporting this claim have had technical limitations, including issues with the specificity of chief cell markers and the toxicity of drugs used. We therefore sought to identify genes expressed specifically in chief cells and establish a model to trace these cells. We performed transcriptome analysis of Mist1 -CreERT–traced cells, with or without chief cell depletion. Gpr30 -rtTA mice were generated and crossed to TetO-Cre mice, and lineage tracing was performed after crosses to R26 -TdTomato mice. Additional lineage tracing experiments were performed using Mist1 -CreERT, Kitl -CreERT, Tff1 -Cre, and Tff2 -Cre mice crossed to reporter mice. Mice were given high-dose tamoxifen or DMP-777 or were infected with Helicobacter pylori to induce gastric metaplasia. We studied mice that expressed mutant forms of Ras in gastric cells, using TetO-KrasG12D, LSL-KrasG12D, and LSL-HrasG12V mice. We analyzed stomach tissues from GPR30 - knockout mice. Mice were given dichloroacetate to inhibit pyruvate dehydrogenase kinase (PDK)–dependent cell competition. We identified GPR30, the G-protein–coupled form of the estrogen receptor, as a cell-specific marker of chief cells in gastric epithelium of mice. Gpr30 -rtTA mice crossed to TetO-Cre; R26 -TdTomato mice had specific expression of GPR30 in chief cells, with no expression noted in isthmus stem cells or lineage tracing of glands. Expression of mutant Kras in GPR30+ chief cells did not lead to the development of metaplasia or dysplasia but, instead, led to a reduction in labeled numbers of chief cells and a compensatory expansion of neck lineage, which was derived from upper Kitl + clones. Administration of high-dose tamoxifen, DMP-777, or H pylori decreased the number of labeled chief cells. Chief cells were eliminated from epithelia via GPR30- and PDK-dependent cell competition after metaplastic stimuli, whereas loss of GRP30 or inhibition of PDK activity preserved chief cell numbers and attenuated neck lineage cell expansion. In tracing studies of mice, we found that most chief cells are lost during metaplasia and therefore are unlikely to contribute to gastric carcinogenesis. Expansion of cells that coexpress neck and chief lineage markers, known as spasmolytic polypeptide-expressing metaplasia, does not occur via dedifferentiation from chief cells but, rather, through a compensatory response from neck progenitors to replace the eliminated chief cells. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the association between proton pump inhibitor (PPI) use and the incidence of intestinal Behçet disease (BD) in patients with BD., Methods: A retrospective cohort study was conducted at The University of Tokyo Hospital, including patients with BD diagnosed between April 2005 and November 2023. Cox models and Kaplan-Meier analyses were used to evaluate hazard ratios (HRs) and cumulative incidence of intestinal BD, respectively. Secondary analyses were performed to assess the duration and dose-response relationship of PPI use., Results: Among 194 patients with BD, 25.3% developed intestinal BD during a mean follow-up of 12 years. PPI users had a significantly higher incidence of intestinal BD compared to nonusers (adjusted HR 2.48, 95% CI 1.38-4.47, P = 0.002), with a confirmed duration/dose-dependent relationship. The cumulative incidence of intestinal BD was markedly elevated in PPI users (log-rank P < 0.001). The result was similar to that in the propensity score-matched cohort., Conclusion: This study demonstrates a significant association between PPI use and increased incidence of intestinal BD in patients with BD. Caution in prescribing PPIs for patients with BD is warranted due to the potential risk of severe complications associated with intestinal BD.

Background & Aims: Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer., Methods: We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-Cre ERT mice., Results: Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19 + luminal surface BECs showed gradual replacement by CK19 - cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2 + PBG cells, but not CK19 + luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor., Conclusion: A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

During human gastric carcinogenesis, intestinal metaplasia is frequently seen in the atrophic stomach. In mice, a distinct type of metaplasia known as spasmolytic polypeptide-expressing metaplasia (SPEM) is found in several inflammatory and genetically engineered models. Given the diversity of long- and short-term models of mouse SPEM, it remains unclear whether all models have a shared or distinct molecular mechanism. The origin of SPEM in mice is presently under debate. It is postulated that stem or progenitor cells acquire genetic alterations that then supply metaplastic cell clones, whereas the possibility of transdifferentiation or dedifferentiation from mature gastric chief cells has also been suggested. In this study, we report that loss of chief cells was sufficient to induce short-term regenerative SPEM-like lesions that originated from chief cell precursors in the gastric neck region. Furthermore, Lgr5 + mature chief cells failed to contribute to both short- and long-term metaplasia, whereas isthmus stem and progenitor cells efficiently contributed to long-term metaplasia. Interestingly, multiple administrations of high-dose pulsed tamoxifen induced expansion of Lgr5 expression and Lgr5-CreERT recombination within the isthmus progenitors apart from basal chief cells. Thus we conclude that short-term SPEM represents a regenerative process arising from neck progenitors following chief cell loss, whereas true long-term SPEM originates from isthmus progenitors. Mature gastric chief cells may be dispensable for SPEM development. NEW & NOTEWORTHY Recently, dedifferentiation ability in gastric chief cells during metaplasia development has been proposed. Our findings reveal that lesions that were thought to be acute metaplasia in fact represent normal regeneration supplied from neck lineage and that isthmus stem/progenitors are more responsible for sustained metaplastic changes. Cellular plasticity in gastric chief cells may be more limited than recently highlighted.